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Genetic defects may affect ability to fight Covid

September 26, 2020 06:50 AM


Genetic defects may affect ability to fight Covid

Sanchita Sharma

New Delhi : One in seven people with severe coronavirus disease (Covid-19) have genetic or immunological defects that affect their ability to fight the virus, according to two new studies that could help explain why some infected people end up in intensive care while others develop no symptoms at all.

The findings were published in the journal Science and suggest genetics could in some part play a role. The researchers said some patients with life-threatening Covid-19 mount a warped immune response because the action of a key molecular messenger called type 1 interferon has been neutralised by either a genetic mutation or by its destruction by an autoimmune attack.

Type 1 interferon leads the battle against infection, mounting an immediate and intense localised response the moment a virus invades a cell. They trigger cells to produce proteins to attack the virus and signal uninfected surrounding cells to strengthen immune defence. Severely-ill Covid patients without interferon have to rely solely on virus-specific adaptive antibodies that develop over days, which gives the virus time to replicate and cause a full-blown infection.

In one of the two new studies, an analysis of blood samples from 987 patients with life-threatening Covid-19 revealed 10.2% had rogue antibodies that attacked and neutralised the patients’ own type 1 interferon, which was undetectable in a subgroup of the patients. Lab studies confirmed the antibodies destroyed the interferon and cells exposed to the patients’ plasma failed to stop infection by Sars-CoV2, the virus that causes Covid-19. Asymptomatic and mild patients did not have these antibodies, which were found in 0.33% of healthy people, the study found.

Another finding was that 94% of the patients with interferon-attacking antibodies were male, which partly explains why men with Covid face higher risk. “Autoimmune disorders are more common in women, but here women may be protected because of the X-chromosome recessive trait, since they have XX chromosomes, and men have XY. This needs to be investigated further,” said immunologist Dr NK Mehra, former dean, All India Institute of Medical Sciences Delhi, and emeritus professor, Indian Council of Medical Research.

The second paper found severely ill patients were more likely to carry a type of mutation leaving them unable to make adequate type 1 interferon to fight Sars-CoV-2. Researchers examined 13 genes because flaws in them impair the body’s production or use of type 1 interferon, and because mutations in them underlie life-threatening influenza or other viral illnesses. Though each such mutation is rare, 3.5% of the critically ill patients collectively harboured rare mutations in eight of those genes.

The analysis, done by the Covid Human Genetic Effort, which is an international consortium working to decipher the molecular, cellular, and immunological mechanisms by which causative monogenic variations cause resistance to viral infection or predisposition to severe disease, did not find the mutation in asymptomatic people and those with mild disease.

Since the known risk factors of Covid severity, which include increasing age after the age of 50, being male and various underlying medical conditions, alone cannot predict disease severity, human genetics are increasing helping demystify the wide variations in Covid-19 disease progression, and many genes, including ones not related to interferon, could affect a person’s response to the virus.

“Our findings suggest that there may be mutations in other type 1 interferon-related genes in other patients with life-threatening Covid-19 pneumonia. They also suggest that the administration of type 1 interferon may be of therapeutic benefit in selected patients, at least early in the course of Sars-CoV-2 infection,” said the study titled, Inborn errors of type I interferon immunity in patients with life-threatening Covid-19, which is the first paper to establish disease-causing mutations as factors for severe Covid-19. Since the auto-antibodies spare one particular form of interferon – the beta form – these patients might also benefit from the experimental treatment with inhaled interferon beta. “These studies are very significant and help explain why innate immunity is on an overdrive and adaptive immunity remains low in Covid-19, while it is the other way around in other viral infections. Innate immunity also mediates the development of a cytokine storm associated with rapid disease progression and death of Covid-19 patients,” said Dr Mehra.

“None of the study participants with mutations or the so-called rogue antibodies had a history of severe viral illnesses, which suggest that we are more reliant on type 1 interferon to protect against Sars-CoV-2 versus other viral infections. Trials on synthetic interferon and therapies that boost interferon action are ongoing, but these won’t work on patients with mutations or those with rogue antibodies that attack them.”

These studies also red flag convalescent plasma therapy since donated plasma may harbour interferon-neutralizing antibodies, which can worsen disease in susceptible people.


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